From brain to bone: Harnessing extracellular vesicles released from TBI to enhance osteogenesis by 3D-Printed hydrogel scaffold

The clinical indications reveal that traumatic brain injury (TBI) accelerates the process of limb bone regeneration. However, the mechanisms underlying this phenomenon remain ambiguous. In this inquiry, the activation of endogenous neural stem cells in the hippocampus post TBI led to the secretion of extracellular vesicles (NSC-EV) that targeted bone marrow mesenchymal stem cells, ultimately promoting bone healing. The enrichment of miR-9-5p in NSC-EV facilitated osteogenesis through the activation of the MAP3K3 pathway. We also present a novel hydrogel formulation for clinical application of NSC-EVs by means of ROS-responsive EV delivery. The hydrogel was cross-linked with EVs to create a water-based gel encapsulation, which was applied to a 3D-printed beta-TCP scaffold for controlled long-term release that corresponded to those of physiological bone tissue. Our investigation represents the inaugural usage of EVs derived from neural stem cells in bone tissue engineering. These EVs were found to encourage information exchange between the central nervous system and bone tissue regeneration. Our composite scaffold demonstrated impressive bone regeneration qualities in rats with cranial defects, highlighting its potential for pioneering approaches in bone tissue engineering and innovative medical technologies for clinical applications.